本論文主要探討銠卟啉和銥卟啉絡合物，分別與酮類與醛類進行的鍵活化化學。 / 第一部分主要介紹由β-乙基羥基銠卟啉絡合物(Rh{U+1D35}{U+1D35}{U+1D35}(ttp)CH₂CH₂OH)與酮類進行的羰基碳及α-碳(C(CO)-C(α)) 鍵活化(下稱碳碳鍵活化)。於室溫至50ºC時，在非溶劑的條件下，Rh{U+1D35}{U+1D35}{U+1D35}(ttp)CH₂CH₂OH選擇性地斷裂芳香酮和脂肪酮類的C(CO)-C(α)鍵，生成相對應的銠卟啉酰基絡合物(Rh{U+1D35}{U+1D35}{U+1D35}(ttp)COR, R = 烷基或芳基)，產率最高可達80%。作為銠卟啉羥基絡合物(Rh{U+1D35}{U+1D35}{U+1D35}(ttp)OH)的前體，Rh{U+1D35}{U+1D35}{U+1D35}(ttp)CH₂CH₂OH的活性展示出Rh{U+1D35}{U+1D35}{U+1D35}(ttp)OH是碳碳鍵活化的重要中間體。 / 第二部分主要介紹由β-乙基羥基銥卟啉絡合物(Ir{U+1D35}{U+1D35}{U+1D35}(ttp)CH₂CH₂OH)與芳香醛類進行，具選擇性的醛碳氫鍵活化。在160ºC和非溶劑的條件下，Ir{U+1D35}{U+1D35}{U+1D35}(ttp)CH₂CH₂OH與芳香醛類反應，生成相對應的銥卟啉酰基絡合物(Ir{U+1D35}{U+1D35}{U+1D35}(ttp)COAr)作為碳氫鍵活化產物，產率最高可達72%。銥卟啉羥基絡合物(Ir{U+1D35}{U+1D35}{U+1D35}(ttp)OH)和乙烯配位銥卟啉絡合正離子((CH₂=CH₂)Ir{U+1D35}{U+1D35}{U+1D35}(ttp)⁺)被推斷為醛碳氫鍵活化的可能中間體。 / This research focuses on the bond activation chemistry by rhodium and iridium porphyrin complexes with ketones and aldehyde respectively. / Part 1 describes the C(CO)-C(α) bond activation (CCA) of ketones by Rh{U+1D35}{U+1D35}{U+1D35}(ttp)CH₂CH₂OH (ttp = 5,10,15,20-tetratolylporphyrinato dianion). Rh{U+1D35}{U+1D35}{U+1D35}(ttp)- CH₂CH₂OH selectively cleaved the C(CO)-C(α) bond of aromatic and aliphatic ketones in solvent-free conditions at room temperature to 50ºC, giving the corresponding rhodium(III) porphyrin acyls (Rh{U+1D35}{U+1D35}{U+1D35}(ttp)COR, R = alkyl or aryl) up to 80% yield. The activity of the Rh{U+1D35}{U+1D35}{U+1D35}(ttp)OH precursor, Rh{U+1D35}{U+1D35}{U+1D35}(ttp)CH₂CH₂OH, demonstrates Rh{U+1D35}{U+1D35}{U+1D35}(ttp)OH as the key intermediate in the CCA of ketones. / [With images]. / Part 2 describes the selective aldehydic carbon-hydrogen bond activation (CHA) of aryl aldehydes by Ir{U+1D35}{U+1D35}{U+1D35}(ttp)CH₂CH₂OH. Ir{U+1D35}{U+1D35}{U+1D35}(ttp)CH₂CH₂OH reacted with aryl aldehydes in solvent-free conditions at 160ºC to give the corresponding iridium(III) porphyrin acyls (Ir{U+1D35}{U+1D35}{U+1D35}(ttp)COAr) as the CHA products up to 72% yield. Ir{U+1D35}{U+1D35}{U+1D35}(ttp)OH and (CH₂=CH₂)Ir{U+1D35}{U+1D35}{U+1D35}(ttp)⁺ were proposed as the possible intermediate for the CHA reaction. / [With images]. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chan, Chung Sum. / "November 2012." / Thesis (M.Phil.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references. / Abstracts also in Chinese. / Abstract --- p.i / Acknowledgement --- p.iii / Table of Contents --- p.iv / Abbreviations --- p.vii / Structural Abbreviations of Porphyrin --- p.viii / Chapter Part 1 --- Carbon-Carbon Bond Activation of Ketones with Rhodium(III) Porphyrin β-Hydroxyethyl --- p.1 / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Properties of Ketones --- p.1 / Chapter 1.2 --- Carbon(CO)-Carbon(α) Bond Activation (CCA) of Ketones --- p.2 / Chapter 1.2.1 --- CCA of Ketones by Transition Metal Complexes --- p.2 / Chapter 1.2.2 --- CCA of Ketones by Metalloporphyrins --- p.5 / Chapter 1.3 --- Porphyrin Ligands and Rhodium(III) Porphyrins --- p.7 / Chapter 1.3.1 --- Porphyrin Ligands --- p.7 / Chapter 1.3.2 --- Rhodium(III) Porphyrins --- p.8 / Chapter 1.4 --- Rhodium(III) Porphyrin Hydroxide --- p.10 / Chapter 1.4.1 --- Nature of Bonding in Late Transition Metal Hydroxides --- p.10 / Chapter 1.4.1.1 --- Hard-Soft Acid-Base principle --- p.11 / Chapter 1.4.1.2 --- dπ-pπ Interaction Model --- p.11 / Chapter 1.4.1.3 --- E-C Model --- p.12 / Chapter 1.4.2 --- Attempted Preparation of Rhodium(III) Porphyrin Hydroxides --- p.13 / Chapter 1.4.3 --- Chemistry of Rhodium(III) Porphyrin Hydroxides --- p.15 / Chapter 1.5 --- Rhodium(III) Porphyrin β-hydroxyethyl as Rhodium(III) Hydroxide Precursor --- p.18 / Chapter 1.6 --- Objective --- p.20 / Chapter Chapter 2 --- Carbon-Carbon Bond Activation of Ketones with Rhodium(III) Porphyrin β-Hydroxyethyl --- p.21 / Chapter 2.1 --- Preparation of Starting Materials --- p.21 / Chapter 2.1.1 --- Synthesis of Porphyrin --- p.21 / Chapter 2.1.2 --- Synthesis of Rhodium(III) Porphyrins --- p.21 / Chapter 2.2 --- CCA of Diisopropyl Ketone by Rh{U+1D35}{U+1D35}{U+1D35}(ttp)CH₂CH₂OH --- p.22 / Chapter 2.3 --- Optimization of Reaction Conditions --- p.22 / Chapter 2.3.1 --- Atmosphere Effect --- p.22 / Chapter 2.3.2 --- PPh3 Effect --- p.23 / Chapter 2.3.3 --- Solvent Effect --- p.24 / Chapter 2.4 --- Substrate Scope --- p.26 / Chapter 2.4.1 --- CCA of Isopropyl Ketones --- p.26 / Chapter 2.4.2 --- CCA of Non-Isopropyl Ketones --- p.28 / Chapter 2.5 --- Proposed Mechanism --- p.29 / Chapter 2.6 --- Comparison on CCA of Ketones by Different Rh{U+1D35}{U+1D35}{U+1D35}(por)OH Sources --- p.31 / Chapter 2.6.1 --- Reaction Conditions --- p.31 / Chapter 2.6.2 --- Substrate Scope --- p.32 / Chapter 2.6.3 --- Regioselectivity --- p.33 / Chapter 2.7 --- Comparison on Bond Activation of Carbonyl Compounds by Rhodium Porphyrin β-Hydroxyethyl --- p.34 / Chapter 2.8 --- CCA of Ketones with Ir{U+1D35}{U+1D35}{U+1D35}(ttp)CH₂CH₂OH --- p.36 / Chapter 2.9 --- Conclusion --- p.37 / Chapter Chapter 3 --- Experimental Sections --- p.39 / References --- p.54 / List of Spectra I --- p.59 / Spectra --- p.60 / Chapter Part 2 --- Aldehydic Carbon-Hydrogen Bond Activation with Iridium(III) Porphyrin β-Hydroxyethyl --- p.63 / Chapter Chapter 1 --- Introduction --- p.63 / Chapter 1.1 --- Properties of Aldehydes --- p.63 / Chapter 1.2 --- Carbon-Hydrogen Bond Activation (CHA) of Aldehydes --- p.64 / Chapter 1.2.1 --- CHA of Aldehydes by Transition Metal Complexes --- p.64 / Chapter 1.2.2 --- Aldehydic CHA by Metalloporphyrins --- p.74 / Chapter 1.3 --- Iridium(III) Porphyrins --- p.77 / Chapter 1.4 --- Iridium(III) Porphyrin Hydroxide --- p.78 / Chapter 1.4.1 --- Attempted Preparation of Iridium(III) Porphyrin Hydroxides --- p.78 / Chapter 1.4.2 --- Chemistry of Iridium(III) Porphyrin Hydroxides --- p.81 / Chapter 1.5 --- Iridium(III) Porphyrin β-hydroxyethyl as Iridium(III) Hydroxide Precursor --- p.83 / Chapter 1.6 --- Objective --- p.85 / Chapter Chapter 2 --- Aldehydic Carbon-Hydrogen Bond Activation with Iridium(III) Porphyrin β-Hydroxyethyl --- p.86 / Chapter 2.1 --- Preparation of Iridium(III) Porphyrins --- p.86 / Chapter 2.2 --- Aldehydic CHA of Benzaldehyde by Ir{U+1D35}{U+1D35}{U+1D35}(ttp)CH₂CH₂OH --- p.87 / Chapter 2.3 --- Optimization of Reaction Conditions --- p.87 / Chapter 2.3.1 --- Temperature Effect --- p.87 / Chapter 2.3.2 --- Solvent Effect --- p.88 / Chapter 2.3.3 --- PPh₃ Effect --- p.90 / Chapter 2.4 --- Substrate Scope --- p.93 / Chapter 2.5 --- Proposed Mechanism --- p.94 / Chapter 2.6 --- Conclusion --- p.96 / Chapter Chapter 3 --- Experimental Sections --- p.97 / References --- p.108 / List of Spectra II --- p.112 / Spectra --- p.112

本文主要探討在有水的條件下，分別以銠卟啉和鈷卟啉絡合物與無張酮反應發生選擇羰基碳及α碳(C(CO)-C(α))鍵活化（下稱碳碳鍵活化）的反應活性和反應機。 / 在200°C，無張芳香和脂肪酮與5, 10, 15, 20-(四甲苯) 銠卟啉絡合物（RhIII(ttp)X，X = Cl 和Me）進反應，生成相對應的碳碳鍵活化產物－銠卟啉酰基絡合物，產最高可達97%。與甲基和乙基酮衍生物相比，丙基酮衍生物有較高的活性,而且丙基酮衍生物的碳碳鍵活化反應甚至能在50°C 的低溫條件下進。 / 根據化學計學，環酮的碳碳鍵開環反應顯示RhIII(ttp)OH 是斷開C(CO)-C(α)鍵的中間體。 / 進一步的反應機研究表明， RhIII(ttp)OH 的羥基是從水中得。RhIII(ttp)X首先進α碳氫鍵活化生成動學產物。經過水解，α碳氫鍵活化產物可以重新形成RhIII(ttp)OH。然後，RhIII(ttp)OH 繼續進碳碳鍵活。 / 另外，經濟的5, 10, 15, 20-(四甲苯) 鈷卟啉絡合物與丙基酮衍生物反應，在室溫下可選擇性進碳碳鍵活化並得到鈷卟啉酰基化合物，產最高達82%。根據化學計學，CoIII(ttp)OH 被認為是碳碳鍵活化的中間體。CoIII(ttp)OH很有可能是通過鈷卟啉與水的歧化反應生成的。 / This thesis focuses on the reactivities and mechanistic studies of the rhodium and cobalt porphyrins (M(por)X) assisted selective carbon(CO)-carbon(α) bond activation (CCA) of unstrained ketones with water. / Unstrained aromatic and aliphatic ketones reacted with 5,10,15,20-tetratolylporphyrinato rhodium(III) complexes, Rh[superscript III](ttp)X (X = Cl and Me), at 200°C to give the corresponding rhodium porphyrin acyls as the CCA products up to 97% yield. Isopropyl ketones exhibit much higher reactivities over methyl and ethyl ketones and the CCA can even occur at a low temperature of 50 °C. / The ring openmg CCA of cyclic ketones suggests the carbon(CO)-carbon(α)bond is cleaved by Rh(ttp )OH according to the reaction stoichiometry. / Further mechanistic investigations suggest that water is the source of hydroxyl group to form Rh[superscript III](ttp)OH. Rh[superscript III](ttp)X first undergoes α-carbon-hydrogen bond activation (α-CHA) to give a kinetic product. Hydrolysis of the α-CHA complex affords Rh[superscript III](ttp)OH for subsequent CCA process. / Alternatively, the economically attractive 5,1 0,15,20-tetratolylporphyrinato cobalt(II) complexes, Co[superscript II](ttp), reacted chemoselectively with isopropyl ketones at the carbon(CO)-carbon(α) bond under room temperature to give high yields of cobalt porphyrin acyls up to 82% yields. Co[superscript III](ttp)OH is identified to be the CCA intermediate as suggested by the reaction stoichiometry. Generation of Co[superscript III](ttp )OH from Co[superscript II](ttp) via the disproportionation with water is proposed. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Fung, Hong Sang. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Abstract --- p.i / Acknowledgements --- p.iv / Table of Contents --- p.v / Abbreviations --- p.ix / Structural Abbreviations for Porphyrins --- p.x / Chapter Chapter 1 --- General Introduction --- p.1 / Chapter 1.1 --- General Introduction to Carbon-Carbon Bond Cleavage --- p.1 / Chapter 1.1.1 --- Organic Examples of Carbon-Carbon Bond Cleavage --- p.1 / Chapter 1.1.2 --- Carbon-Carbon Bond Activation with Transition Metal 2Complexes --- p.2 / Chapter 1.1.2.1 --- Ring Strain Relief --- p.2 / Chapter 1.1.2.2 --- Chelation Assistance --- p.3 / Chapter 1.1.2.3 --- Aromatization --- p.3 / Chapter 1.1.2.4 --- Carbonyl Functionality --- p.4 / Chapter 1.1.2.5 --- β-Alkyl Elimination --- p.4 / Chapter 1.1.2.6 --- Formal Alkane Metathesis --- p.5 / Chapter 1.2 --- Carbon-Carbon Bond Cleavage of Ketones --- p.6 / Chapter 1.2.1 --- Properties of Ketones --- p.6 / Chapter 1.2.2 --- Organic Examples of Carbon-Carbon Bond Cleavage of Ketones --- p.7 / Chapter 1.2.2.1 --- Haloform Reaction --- p.8 / Chapter 1.2.2.2 --- Haller-Bauer Reaction --- p.8 / Chapter 1.2.2.3 --- Baeyer-Villiger & Dakin Oxidation --- p.9 / Chapter 1.2.2.4 --- Beckmann & Schmidt Rearrangement --- p.10 / Chapter 1.2.2.5 --- Favorskii Rearrangement --- p.11 / Chapter 1.2.2.6 --- Norrish Type I Reaction --- p.12 / Chapter 1.2.2.7 --- Hydrolysis with Water --- p.12 / Chapter 1.2.3 --- Carbon(CO)-Carbon(α) Bond Activation of Ketones with Transition Metal Complexes --- p.13 / Chapter 1.2.3.1 --- Stoichiometric C(CO)-C(α) Bond Activation of Ketones --- p.18 / Chapter 1.2.3.1.1 --- Metal Insertion into Strained Ring --- p.18 / Chapter 1.2.3.1.2 --- Decarbonylation --- p.19 / Chapter 1.2.3.1.3 --- Chelation Assisted CCA of Unstrained Ketones --- p.19 / Chapter 1.2.3.1.4 --- Reaction with Benzyne Complex --- p.20 / Chapter 1.2.3.1.5 --- Reaction with Metal Hydroxide --- p.21 / Chapter 1.2.3.2 --- Catalytic C(CO)-C(α) Bond Activation of Ketones --- p.22 / Chapter 1.2.3.2.1 --- Decarbonylation --- p.22 / Chapter 1.2.3.2.2 --- Insertion with Unsaturated Compounds --- p.23 / Chapter 1.2.3.2.3 --- Hydrogenolysis --- p.24 / Chapter 1.2.3.2.4 --- Ring Fusion --- p.25 / Chapter 1.3.3.2.5 --- [4+2+2] Annulation --- p.26 / Chapter 1.2.3.2.6 --- Alcoholysis and Aminolysis --- p.27 / Chapter 1.2.3.2.7 --- Hydroarylation --- p.28 / Chapter 1.2.3.2.8 --- Arylative Ring Expansion with Alkynes --- p.29 / Chapter 1.3 --- Water as An Oxidizing Agent --- p.29 / Chapter 1.3.1 --- Water-Gas Shift Reaction --- p.30 / Chapter 1.3.2 --- Hydration of C-C π-Bond --- p.31 / Chapter 1.3.3 --- Cleavage of C≡C Bond --- p.31 / Chapter 1.3.4 --- Oxidation of C-H Bond --- p.32 / Chapter 1.4 --- Transition Metal Hydroxide Chemistry --- p.33 / Chapter 1.4.1 --- Preparation of Group 9 Metal Hydroxides --- p.34 / Chapter 1.4.1.2 --- Ligand Substitution --- p.34 / Chapter 1.4.1.3 --- Oxidative Addition --- p.34 / Chapter 1.4.1.4 --- Hydrolysis --- p.35 / Chapter 1.4.2 --- Chemistry of Transition Metal Hydroxide --- p.35 / Chapter 1.5 --- Introduction to Porphyrins and Group 9 Metalloporphyrins --- p.37 / Chapter 1.5.1 --- Porphyrin Ligand --- p.37 / Chapter 1.5.2 --- Metalloporphyrins --- p.38 / Chapter 1.5.3 --- Chemistry of Group 9 Metalloporphyrins --- p.39 / Chapter 1.5.3.1 --- M[superscript I](por) Chemistry --- p.40 / Chapter 1.5.3.2 --- M[superscript II](por) Chemistry --- p.41 / Chapter 1.5.3.3 --- M[superscript III](por) Chemistry --- p.44 / Chapter 1.5.4 --- Equilibration of MI(por), MI (por) and MIII(por) --- p.46 / Chapter 1.5.5 --- Chemistry of Group 9 Metalloporphyrin Hydroxide --- p.47 / Chapter 1.5.5.1 --- Metalloether Formation --- p.47 / Chapter 1.5.5.2 --- Reductive Dimerization --- p.48 / Chapter 1.5.5.3 --- Oxidation --- p.49 / Chapter 1.5.5.4 --- Carbon-Hydrogen Bond Activation --- p.50 / Chapter 1.5.5.5 --- Carbon-Carbon Bond Activation --- p.51 / Chapter 1.6 --- Scope of Thesis --- p.52 / Chapter Chapter 2 --- Carbon(CO)-Carbon(α) Bond Activation of Ketones with Rhodium(lII) Porphyrin Complexes --- p.63 / Chapter 2.1 --- Introduction --- p.63 / Chapter 2.2 --- Objectives of the Work --- p.66 / Chapter 2.3 --- Preparation of Starting Materials --- p.66 / Chapter 2.3.1 --- Synthesis of Porphyrin --- p.66 / Chapter 2.3.2 --- Synthesis of Rhodium(III) Porphyrin Chloride --- p.67 / Chapter 2.3.3 --- Synthesis of Rhodium(III) Porphyrin Methyl --- p.67 / Chapter 2.3.4 --- Synthesis of Rh[superscript III](ttp)H --- p.68 / Chapter 2.3.5 --- Synthesis of Rh[superscript II]₂(ttp)₂ --- p.68 / Chapter 2.3.6 --- Synthesis of Rh[superscript I](ttp)-Na⁺ --- p.68 / Chapter 2.4 --- Optimization of Reaction Conditions with Acetophenone --- p.68 / Chapter 2.4.1 --- Reaction with Rh[superscript III](ttp )OTf, Rh[superscript III](ttp)Cl and Rh[superscript III](ttp)Me --- p.68 / Chapter 2.4.2 --- Temperature Effect --- p.70 / Chapter 2.4.3 --- Porphyrin Ligand Effect --- p.70 / Chapter 2.5 --- Substrate Scope of the CCAReaction --- p.71 / Chapter 2.5.1 --- CCA of Acetophenones --- p.71 / Chapter 2.5.2 --- CCA of Aromatic and Aliphatic Ketones --- p.72 / Chapter 2.6 --- Low Temperature CCA with Isopropyl Ketones --- p.76 / Chapter 2.7 --- Oxidation of the C(CO)-C(α) Bond --- p.77 / Chapter 2.8 --- Water as a Source of Oxidant --- p.80 / Chapter 2.9 --- Regioselectivity of CCA --- p.81 / Chapter 2.1 --- 0 X-ray Structure Determination --- p.83 / Chapter 2.11 --- Mechanistic Studies --- p.92 / Chapter 2.11.1 --- Proposed Mechanism --- p.92 / Chapter 2.11.2 --- Aldol Condensation Catalyzed by Rh(ttp)X (X = Me or Cl) --- p.93 / Chapter 2.11.3 --- Carbon-Hydrogen Bond Activation with Rh(ttp)X (X = Me or Cl) --- p.94 / Chapter 2.11.4 --- Hydrolysis of the α-CHA Product 100 --- p.100 / Chapter 2.11.5 --- Carbon(CO)-Carbon(α) Bond Oxidation with Rh(ttp)OH --- p.102 / Chapter 2.11.6 --- Dehydrogenation of Alcohol --- p.108 / Chapter 2.11.7 --- Thermodynamic Consideration --- p.109 / Chapter 2.12 --- Conclusion --- p.110 / Chapter Chapter 3 --- Carbon(CO)-Carbon(α) Bond Activation of Ketones with Cobalt(II)Porphyrin Complexes --- p.114 / Chapter 3.1 --- Introduction --- p.114 / Chapter 3.2 --- Objectives of the Work --- p.115 / Chapter 3.3 --- Preparation of Starting Materials --- p.115 / Chapter 3.3.1 --- Synthesis of H₂(tp-clPP) --- p.115 / Chapter 3.3.2 --- Synthesis of Co[superscript II] (por) --- p.116 / Chapter 3.4 --- Strategies of C(CO)-C(α) Bond Activation with Cobalt(II) Porphyrins --- p.116 / Chapter 3.5 --- Optimization of Reaction Conditions with Diisopropyl Ketone --- p.118 / Chapter 3.5.1 --- Solvent Effect --- p.118 / Chapter 3.5.2 --- Water Effect --- p.119 / Chapter 3.5.3 --- PPh3 Effect --- p.120 / Chapter 3.5.4 --- Porphyrin Ligand Effect --- p.121 / Chapter 3.5.5 --- Temperature Effect --- p.122 / Chapter 3.6 --- CCA of Isopropyl Ketones --- p.123 / Chapter 3.7 --- X-ray Structure Determination --- p.126 / Chapter 3.8 --- Mechanistic Studies --- p.131 / Chapter 3.8.1 --- Proposed Mechanism --- p.131 / Chapter 3.8.2 --- Disproportionation of Co[superscript II](ttp) with Water --- p.132 / Chapter 3.8.3 --- Dehydrogenation of Co[superscript III](ttp)H --- p.132 / Chapter 3.8.4 --- C(CO)-C(α) Bond Activation --- p.134 / Chapter 3.8.5 --- Dehydrogenation of the Alcohol --- p.134 / Chapter 3.8.6 --- Overall Enthalpy Change --- p.134 / Chapter 3.9 --- Stoichiometric Functionalization --- p.135 / Chapter 3.10 --- Conclusion --- p.138 / Chapter Chapter 4 --- Comparison on Carbon-Carbon Bond Activation by Cobalt, Rhodium and Iridium Porphyrin --- p.142 / Chapter 4.1 --- Introduction --- p.142 / Chapter 4.2 --- Reactivities of Metalloporphyrins --- p.143 / Chapter 4.3 --- Thermodynamic of CCA --- p.144 / Chapter 4.4 --- Rate of CCA --- p.147 / Chapter 4.5 --- Scope and Reactivities of Ketones --- p.147 / Chapter 4.6 --- Regioselectivities --- p.149 / Chapter 4.7 --- Chemoselectivity --- p.150 / Chapter 4.8 --- Conclusion --- p.152 / Chapter Chapter 5 --- Experimental Section --- p.153 / Appendices --- p.181

As porfirinas e seus derivados têm sido, ao longo dos anos, alvos de vários campos diferentes de interesse, obtendo diversas aplicações, as quais tem aumentado constantemente com o decorrer dos anos. Dentre suas aplicações, uma das mais importantes se encontra no campo da Medicina moderna, sendo a principal na área de detecção e extirpação de tecidos modificados, a partir da Terapia Fotodinâmica (do termo inglês Photodynamic Therapy – PDT), apresentando resultados promissores. Em diversos processos biológicos, as porfirinas podem existir na forma monomérica ou na forma agregada. Entretanto, a agregação de porfirinas reduz sua eficiência nas aplicações em PDT devido a redução dos tempos de vida e rendimentos quânticos de produção dos estados excitados singleto e tripleto e levando, conseqüentemente, a redução na produção de oxigênio singleto. Diversos fatores influenciam o processo de agregação das porfirinas. Dentre eles, a interação eletrostática exerce um importante papel. A modulação dessa interação pode tanto estimular a agregação, quanto diminuir a probabilidade de formação dos agregados. Deste modo, condições externas, tais como pH, força iônica e especialmente a interação com sistemas microheterogêneos podem modificar essa interação e influenciar também nas características de agregação. Neste trabalho buscamos avaliar, através de diversos métodos espectroscópicos, os efeitos da interação das porfirinas meso-tetrakis (p-sulfonatofenil) porfirina (TPPS4), aniônica, e meso-tetrakis (4-N-metilpiridil) porfirina (TMPyP), catiônica, com sistemas microheterogêneos naturais e sintéticos (células “ghost" de eritrócitos e micelas) em função da sua própria estrutura, da estrutura destes sistemas e de fatores externos (concentração, pH, força iônica). O interesse principal foi dedicado aos efeitos dessa interação na formação de agregados das porfirinas. Foram analisadas as mudanças nas características fotofísicas e fotoquímicas destes compostos, tais como espectros de absorção, rendimentos quânticos e tempos de vida dos estados excitados singleto e tripleto, produção de oxigênio singleto, etc, visando obter informações sobre o comportamento coletivo dessas porfirinas, o que é muito importante para as suas possíveis aplicações em medicina, em particular na Terapia Fotodinâmica do câncer. Foi descoberto que a interação da porfirina aniônica TPPS4 com micelas de carga oposta ou na presença de alta força iônica em pH < pKa estimula a formação seqüencial de dois tipos de agregados: inicialmente são formados agregados H que após certo período se transformam em agregados J. A formação desses agregados altera os espectros de absorção, rendimentos quânticos e tempos de vida dos estados excitados singleto e tripleto e produção de oxigênio singleto. Foi observado que a interação com porfirinas altera a c.m.c dos tensoativos, reduzindo em até três ordens de grandeza o valor da c.m.c dos tensoativos de carga oposta à das porfirinas. Associamos esta c.m.c com a formação de micelas mistas porfirina+tensoativo. Foi também observado que a adição de NaCl no sistema porfirina+micelas ou porfirina+células ghost facilita a penetração da porfirina no interior da micela ou membrana, diminuindo assim a probabilidade de contato entre as porfirinas e o oxigênio, reduzindo a constante bimolecular de supressão do estado tripleto da porfirina pelo O2. A fim de avaliar a influência da estrutura dos fotossensibilizadores (FS) na sua fototoxicidade, comparamos o efeito fototóxico de ambas porfirinas e dois corantes bisciânicos em células de linhagem neoplásica HT29. Os resultados foram analisados levando em consideração as características de ligação dos FS, sua penetração e localização nas células HT29. A fototividade de ambas porfirinas em cultura celular demonstrou ser independente do tipo de suas cargas, apresentado um perfil de toxicidade muito similar. Os BCDs apresentaram uma elevada toxicidade em comparação com a das porfirinas. Observamos que as porfirinas e os BCDs possuem uma cinética de acumulação muito similar e períodos de ligação muito próximos (2h). Entretanto, o tempo e o local de internalização parecem ser dependentes tanto da estrutura quanto da carga do FS. Assim, os BCDs se internalizaram após apenas 2 horas e se localizaram preferencialmente nas mitocôndrias. Por outro lado, a TPPS4 localiza-se principalmente nos lisossomos enquanto que a TMPyP parece estar localizada na membrana celular, ambas com um tempo de internalização de 24 horas. Estes resultados podem explicar a elevada fototoxicidade dos BCDs observada em nossos experimentos. / During several decades the porphyrins and their derivatives continue of interest in different areas including various applications, the number of which is increasing with time. One of their most important applications is in modern medicine to detect and extirpate modified tissues, the photodynamic therapy (PDT) being the principle area, which demonstrates promising results. Taking part of various biological processes, the porphyrins may exist as monomers or aggregates. However, aggregation reduces their efficacy in PDT as it shortens their lifetimes and quantum yields of excited singlet and triplet states, thus reducing the production of singlet oxygen. There exist various factors, which may modify aggregation of the porphyrins, the electrostatic interaction being very important. Modulation of this interaction can stimulate aggregation or reduce the probability of the aggregate formation. So external conditions such as pH, ionic strength and interaction with microheterogeneous systems can modify this interaction and thus affect the aggregation characteristics. In this work we present the results received with the help of various spectroscopic techniques on interaction of anionic meso-tetrakis (p-sulfonatophenyl) (TPPS4) and cationic meso-tetrakis (4-N-methyl-pyrydiumil) (TMPyP) porphyrins with natural and synthetic microheterogeneous systems (“ghost" erythrocyte membranes and micelles) in function of their proper structure, the structure of these systems and the external factors (concentration, pH, ionic strength). The principle attention was paid to the effects of this interaction on aggregation of the porphyrins. We analyzed variations in the porphyrin photophysical and photochemical characteristics such as absorption spectra, quantum yields and lifetimes of excited singlet and triplet states, singlet oxygen production, etc., to look for the regularities in their collective behavior which is very important at their possible application in medicine, in PDT of cancer, in particular. We found that the interaction of the anionic porphyrin TPPS4 with micelles of the opposite charge or in the presence of high ionic strength at pH<pKa stimulated sequential formation of two types of aggregates: at the beginning H aggregates were formed which transformed with time in J type. Formation of the aggregates modified the porphyrin absorption spectra, their lifetimes and quantum yields of excited singlet and triplet states and the production of singlet oxygen, as well. We observed that the interaction with porphyrins reduced up to three orders of magnitude the c.m.c. values for surfactants with the charge opposite to that of the porphyrin. We attribute these reduced c.m.c. values to formation of mixed micelles (surfactant + porphyrin). We observed that in the presence of NaCl in the systems (porphyrin + micelle) or (porphyrin + “ghost" cells) the dye penetrated more easily the interior of the micelle or the membrane, reducing the probability of its contact with oxygen, and, hence, reducing the bimolecular constant of triplet suppression by O2. To evaluate the influence of the structure of photosensitizers (PS) on their phototoxicity we compared phototoxic effects of both porphyrins and two biscyanine dyes upon the neoplasic cells line HT29. The results were analyzed taking into account the characteristics of photosensitizer binding, penetration and localization in cells. The photoefficacy of both porphyrins was demonstrated independent of the type of their charge, their phototoxicities being very close. The BCDs demonstrated the elevated phototoxicity as compared with that of porphyrins. We observed that both porphyrins and BCDs possessed very close accumulation kinetics and their binding periods were similar (2 h). Nevertheless, the time of the PS entrance to the cell and their intracellular localization were shown to depend on their structure and charge. So, the BCDs entered the cell in two hours and were localized preferably in mitochondrias. The TPPS4 localized in lysosomes, while TMPyP seemed to prefer the cell membrane, the time of entrance for both being close to 24 hours. These results may explain higher BCDs phototoxicity observed in the experiments.

Uma série de porfirinas meso-substituídas tetracatiônicas foi sintetizada e caracterizada, com o objetivo de estudar o papel da anfifilicidade e a presença de zinco em propriedades que podem influenciar na eficácia dos mesmos como FSs na terapia fotodinâmica. Observamos que as propriedades fotofísicas dos compostos são semelhantes (máximos de absorção na mesma região, red. quantico fl0,02; rend. quantico ox. singlete ~0.8). O aumento na lipofilicidade e a presença de zinco no centro do anel porfirínico aumentam a incorporação dos FSs em vesículas e células, uma vez que a presença de zinco possibilita a coordenação pelos grupos fosfato dos fosfolipídeos (os resultados os estudos das monocamadas de Langmuir e dos filmes de Langmuir-Blodgett corroboram com esta afirmação). A incorporação em mitocôndrias é também dependente da lipofilicidade do FS e é influenciada pelo potencial eletroquímico de membrana. A presença do zinco mostrou diminuir a incorporação em mitocôndrias isoladas e em mitocôndrias nas células HeLa, devido às características particulares da membrana mitocondrial interna. A fototoxicidade aumenta proporcionalmente ao aumento da eficiência da incorporação em membranas, que é atribuída às interações favoráveis entre os FSs e as membranas, permitindo a fotooxidação mais eficiente das mesmas. Para esta série de compostos, a eficiência fotodinâmica é diretamente proporcional à ligação em membranas e incorporação em células, mas não está totalmente relacionada ao acúmulo seletivo em mitocôndrias. Os resultados preliminares de permeação e retenção cutâneos mostram que apesar destes FSs apresentarem baixa penetração e retenção na pele, quando adequadamente formuladas passam a apresentar penetração e retenção cutâneas adequadas de maneira que poderiam ser utilizados na TFD tópica no tratamento de câncer de pele. / A series of photosensitizers (PS), which are meso-substituted tetra-cationic porphyrins, was synthesized and characterized in order to study the role of amphiphilicity and zinc insertion in PDT efficacy. The photophysical properties of all compounds are quite similar (absorption maxima in the same region of the spectra, f 0.02; ~0.8). An increase in lipophilicity and the presence of zinc in the porphyrin ring result in higher vesicle and cell uptake, because zinc can be complexed by the phosphate groups of the phospholipids. The results from the study of Langmuir monolayers and Langmuir-Blodgett mixed films corroborate this affirmation. Binding in mitochondria is dependent on the PS lipophilicity and on the electrochemical membrane potential. Zinc insertion was also shown to decrease the interaction with isolated mitochondria and with the mitochondria of HeLa cells, an effect that has been explained by the particular characteristics of the mitochondrial internal membrane. Phototoxicity was shown to increase proportionally with membrane binding efficiency, which is attributed to favorable membrane interactions between FSs and membranes, which allow for more efficient membrane photooxidation. For this series of compounds, photodynamic efficiency is directly proportional to membrane binding and cell uptake, but it is not totally related to mitochondrial targeting. Preliminary results of skin permeation and retention show that besides presenting low permeation and retention when suitably formulated, FSs can cross the EC barrier and accumulate in deeper regions, thus being applicable to topical PDT in the treatment of skin cancer.

A síntese, caracterização e propriedades fotofísicas e fotoquímicas de uma série de meso-(fenilpiridil)porfirinas, com n substituintes fenila e 4-n substituintes piridina (n = 1 a 4), e as respectivas espécies supermoleculares obtidas pela coordenação de complexos [Ru(2,2\'-bipy)2Cl]+ aos nitrogênios piridínicos, são descritos. Os resultados dos estudos espectroscópicos e eletroquímicos foram consistentes com as estruturas propostas. Foi constatada a ocorrência de processo de transferência de energia do estado MLCT3 dos complexos periféricos para o estado singlete da porfirina em vidro de etanol, e para o estado triplete a 25°C. Esses resultados sugerem que o estado excitado MLCT3 está energeticamente acima do estado S1, a 77 K, e existe uma interação eletrônica significativa entre os complexos de rutênio e o anel porfirínico. A temperatura ambiente, a transferência de energia para o estado singlete da porfirina é ineficiente devido a rápida desativação não radiativa do estado MLCT3. Esse fato foi confirmado pelo espectro de excitação, que reproduz apenas as bandas de absorção da porfirina. O rendimento quântico de fluorescência da porfirina sofre uma diminuição bastante pronunciada quando em presença de O2 dissolvido, que parecem ser inversamente proporcionais ao número de substituintes piridina. Além disso, o tempo de vida, a constante de velocidade de supressão pelo O2 e o rendimento quântico de formação de oxigênio singlete a partir da espécie no estado triplete T1, parecem não ser influenciados pelo número de complexos [Ru(bipy)2Cl]+ coordenados ao anel porfirínico. Nenhuma fotodecomposição foi observada durante os experimentos. Os rendimentos quânticos de oxigênio singlete (~O,5) obtidos para as porfirinas supermoleculares são comparável ao de outros fotossensibilizadores porfirínicos utilizados em estudos de terapia fotodinâmica. Logo, a estratégia de se introduzir complexos de rutênio bipiridina como modificadores das propriedades das meso(fenilpiridil)porfirinas, e também como novos sítios de interação, por exemplo, com biomoléculas, parece ser adequada para a preparação de novos sensibilizadores supramoleculares. / The preparation, characterization and photophysical and photochemical properties of a series of meso-(phenylpyridyl)porphyrins, with n phenyl and 4n pyridyl substituents (n =1 to 4), and the respective supermolecular species obtained by the coordination of [Ru{2,2\'-bipy)2Cl]+ complexes to the pyridine nitrogen atoms, are described. The results of the spectroscopic and electrochemical studies were consistent . with the proposed molecular structures. The occurrence of energy transfer processes from the MLCT3 state of the peripheral ruthenium complexes to the porphyrin singlet state in ethanol glass, and to the triplet state at room temperature, were observed. These strongly suggest that the excited MLCT3 state is energetically above the porphyrin S1 state (77 K), and that there is a sufficiently strong electronic interaction between the ruthenium complexes and the porphyrin ring. The energy transfer from MLCT3 to the porphyrin S1 state is inefficient at room temperature, because ofthe fast non-radiactive deactivation of that excited state. This was confirmed by the excitation spectra, that exhibited only the absorption bands ofthe porphyrin moiety. The fluorescence quantum yield of the porphyrin is decreased in presence of dissolved O2, and this behavior seems to be inversely proportional to the number of pyridyl substituents. Furthermore, the lifetime, the quenching rate constant by 02 and the singlet oxygen quantum yields for the porphyrin triplet state, seems to be independent of the number of [Ru(bipy)2Cl]+ complexes coordinated to the ring. No photodecomposition were observed during the above experiments. The singlet oxygen quantum yields (~O,5) determined for the supermolecular porphyrins are comparable to that of other porphyrin type photosensitizers used in studies on photodynamic terapy. Consequently, the strategy of coordinating ruthenium bipyridyl complexes as modifiers ofthe meso-(phenylpyridyl)porphyrins and also as new interaction sites, for example for biomolecules, seems adequate for the preparation of new supermolecular photosensitizers.

A síntese e a caracterização de uma série de porfirinas polinucleares, por meio de análise elementar, espectroscopia eletrônica e Raman ressonante, voltametria cíclica e espectroeletroquímica, são apresentadas nesta tese. Estas supermoléculas foram obtidas pela coordenação de quatro grupos Ru(edta)- ou Ru(bipY)2Cl+ aos resíduos piridínicos das meso-tetra(piridil)porfirinas base-livre e metaladas. As propriedades eletrocatalíticas, fotoquímicas e fotofísicas foram estudadas, dando especial atenção às propriedades supramoleculares resultantes da interação entre as porfirinas e os complexos de rutênio periféricos. Também, foi explorada a capacidade singular desses complexos de formar filmes. Estes materiais são excelentes condutores iônicos e eletrônicos, e se comportam como fotocondutores moleculares, possibilitando a conversão de energia luminosa em elétrica. A possibilidade de utilizar estes filmes na confecção de dispositivos, tais como retificadores, amplificadores e transístores, assim como, células fotoelétricas e fotoeletroquímicas, abre novas perspectivas na área da fotoeletrônica molecular. / The synthesis and characterization of a series of polynuclear porphyrins by elementary analysis, electronic and resonance Raman spectroscopy, cyclic voltanunetry and spectroelectrochemistry, are presented. Those supermolecules were obtained by attaching Ru( edta)- or Ru(bipY)2Cl+ groups to the four pyridine residues of the free-base or the metallated meso-tetra(pyridil)porphyrins. Their electrocatalytical, photochemical and photophysical properties were studied. Special attention were paid to the supramolecular properties resulting from the interaction of the porphyrin and the peripheral ruthenium complexes. The unusual ability of these complexes to form stable films was also explored. These materials are excellent ionic and electronic conductors and act as molecular photoconductors, converting light into electricity. The films can be used for the design of electronic devices such as rectifiers, amplifiers and transistors, as well as, of photoelectric and photoelectrochemical cells.

Uma série de compostos de transferência de carga baseado em derivados de anilina (grupo doador) e N-alquilpiridínio (grupo receptor) foi preparada e ligada à periferia do anel porfirínico, gerando uma nova série de porfirinas supermoleculares, que foram caracterizadas por espectroscopia eletrônica, voltametria cíclica, espectroeletroquímica, fluorescência e fotólise relâmpago. Os compostos foram preparados no laboratório do Prof. Silviu Balaban, no Instituto de Nanotecnologia do Forschungszentrum Karlsruhe, visando o estudo da interação entre a porfirina e aqueles compostos de transferência de carga, particularmente o efeito da estrutura molecular sobre as as propriedades fotoquímicas. As porfirinas foram projetadas tendo como modelo o sistema antena de algumas bactérias verdes fotossintéticas, visando obter fotossensibilizadores mais eficientes acoplando processos de transferência de energia (efeito antena) para o sítio porfirínico ativo, aumentando a eficiência de absorção/conversão na região do visível, melhorando assim o aproveitamento da energia solar. De fato, os sensibilizadores porfirínicos supermoleculares que foram objeto de estudo desta tese, apresentaram apenas um eficiente mecanismo de transferência de energia intramolecular para o grupo porfirínico; e as ligações amida ou éster utilizadas para ligar os grupos parecem não influenciar significativamente a eficiência do efeito antena. Os estudos de fluorescência e de fotólise relâmpago indicaram que os estados excitados singlete e triplete de menor energia estão localizados na porfirina, e que não há competição significativa de processos paralelos de supressão do estado excitado, por exemplo pelo mecanismo redox, apesar dos potenciais serem termodinamicamente favoráveis. Porém, pode haver transferência de carga do grupo derivado de anilina para a porfirina oxidada após a injeção de elétrons fotoinduzida para o filme de TiO2 nanocristalino, melhorando o processo de separação de cargas. Em suma, os materiais porfirínicos apresentam características adequadas e potencialidade para uso como fotossensibilizadores em dispositivos fotoeletroquímicos e fotovoltáicos. / A series of charge-transfer compounds constituted by anilline and Nalkylpyridynium derivatives as donor and acceptor groups was prepared and bond to the meso-position of a porphyrin to get a new series of supermolecular porphyrins, that were characterized by UV-Vis and fluorescence spectroscopy, cyclic voltammetry, spectroelectrochemistry and flash-photolysis. The series of compounds were synthesized in the Prof. Silviu Balaban Lab, at the Forschungszentrum Karlsruhe Institute of Nanotechnology aiming the study of the properties coming out of the interaction of porphyrins and donor-acceptor charge-transfer complexes, particularly the influence of the molecular structure on the photophysical properties. The supermolecular porphyrins were designed using the antenna system of photosynthetic green bacteria as model, in order to obtain more efficient photosensitizers by enhancing the light harvesting efficiency of porphyrins incorporating the energy-transfer effect. In fact, the charge-transfer complexes bound to the porphyrin ring were shown to interact exclusively through energy-transfer, and the amide or esther used to bridge those components didnt influence significantly the efficiency of that process. The lowest excited state was found to be localized on the porphyrin ring in the singlet and triplet excited state, by fluorescence and flashphotolysis studies. More interestingly, the results indicated that there is no competition of parallel deactivation mechanisms, such as redox mechanism, even though the potentials are thermodynamically favorable. However, charge-transfer from the donor anilline derivatives to the oxidized porphyrin site can take place immediately after photoinduced injection of an electron to nanocrystalline TiO2, improving the charge-separation process. In conclusion, the supermolecular porphyrins exhibited suitable properties as photosensitizers in photoelectrochemical and photovoltaic devices.

*Please refer to dissertation for diagrams. / Part I describes the silicon-hydrogen bond activation (SiHA) of silanes with both electron-deficient iridium porphyrin carbonyl chloride (Ir(ttp)Cl(CO)) and electron-rich iridium porphyrin methyl (Ir(ttp)Me) to give iridium(III) porphyrin silyls (Ir(ttp)SiR3). Firstly, Ir(ttp)SiR3 were synthesized in moderate to good yields conveniently from the reactions of Ir(ttp)Cl(CO) and Ir(ttp)Me with silanes, via SiHA in solvent-free conditions and non-polar solvents at 200&deg;C. Base facilitated the SiHA reaction even at lower temperature of 140&deg;C. Specifically, K3PO4 accelerated the SiHA with Ir(ttp)Cl(CO), while KOAc promoted the SiHA by Ir(ttp)Me. Mechanistic experiments suggest that Ir(ttp)Cl(CO) initially forms iridium porphyin cation (Ir(ttp)+), which then reacts with silanes likely via heterolysis to give iridium porphyrin hydride (Ir(ttp)H). Ir(ttp)H further reacts with silanes to yield Ir(ttp)SiR3. On the other hand, Ir(ttp)Me and Ir(ttp)SiR3 undergo either oxidative addition (OA) or sigma-bond metathesis (SBM) to form the products. In the presence of base, a penta-coordinated silicon hydride species likely forms and reacts with Ir(ttp)Me to form iridium porphyrin anion (Ir(ttp) -) that can further react with silane to yield Ir(ttp)H after protonation. Ir(ttp)H finally reacts with excess silane to give Ir(ttp)SiR 3.* / Part II describes successful base promoted aromatic carbon-fluorine (C-F) and carbon-hydrogen (C-H) bond activation of fluorobenzenes in neat conditions to give the corresponding iridium(III) porphyrin aryls (Ir(ttp)Ar) at 200&deg;C in up to 95% yield. Mechanistic studies suggested that Ir(ttp)SiEt3 is firstly converted to Ir(ttp)- in the presence of KOH. Ir(ttp)- cleaves the aromatic C-F bond via an S NAr process. As the reaction proceeds, a hydroxide anion can coordinate to the iridium center of Ir(ttp)Ar to form an iridium porphyrin trans aryl hydroxyl anion (trans-[ArIr(ttp)OH]-). In the presence of water, trans-[ArIr(ttp)OH]- can give Ir(ttp)OH and ArH. Ir(ttp)OH then undergoes aromatic C-H bond activation reaction to give Ir(ttp)Ar'. Furthermore, the aromatic C-F bond activation products were found as the kinetic products, and aromatic C-H bond activation products were the thermodynamic ones.* / Part III describes the successful C(C=O)-C(alpha) bond activation of acetophenones by high-valent iridium porphyrin complexes (Ir(ttp)X, X = Cl(CO), (BF4)(CO), Me) in solvent-free conditions at 200&deg;C to give the corresponding iridium porphyrin benzoyls (Ir(ttp)COAr) in up to 92% yield. Mechanistic studies suggest that Ir(ttp)X reacts with acetophenones to give alpha-CHA product as the primary product, which can re-convert back to the active intermediate Ir(ttp)OH or Ir(ttp)H in the presence of water formed from the concurrent iridium-catalyzed aldol condensation of acetophenones. Then Ir(ttp)OH cleaves the aromatic C-H bonds to produce the aromatic CHA products, which are more thermally stable than the alpha-CHA product. Both Ir(ttp)H and Ir(ttp)OH were the possible intermediates to cleave the C(C=O)-C(alpha) bond to give thermodynamic products of Ir(ttp)COAr. On the other hand, only Ir(ttp)(BF 4)(CO) can react with the aliphatic ketones, likely due to the stronger Lewis acidity and the HBF4 generated in catalyzing the aldol condensation of aliphatic ketones to facilitate the formation of Ir(ttp)OH and Ir(ttp)H.* / The objectives of the research focus on the bond activation chemistry by iridium porphyrin complexes with three organic substrates, (1) hydrosilanes (HSiR3), (2) fluorobenzenes (C6HnF6-n , n = 0--6), and (3) aromatic or aliphatic ketones (RCOR, R = alkyl or aryl). / Li, Baozhu. / Adviser: Kin Shing Chan. / Source: Dissertation Abstracts International, Volume: 72-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese.

Pancreatic cancer kills over 1700 people each year in Australia. In 2000, there were 1908 new cases diagnosed and it remains one of the least treatable malignancies. In the USA, it was the fourth leading cause of cancer death in 2004, with 31,860 new cases and 31,270 recorded deaths. Photodynamic therapy (PDT) is a novel, potentially useful treatment for locally advanced pancreatic cancer with only limited research and clinical work addressing this until now. PDT induces non-thermal, cytotoxic and ischaemic injury to a targeted volume of tissue. During PDT, a photosensitizer is activated by non-thermal light in the presence of oxygen, generating cytotoxic oxygen species and inducing cellular injury and microvascular occlusion. The aim of this thesis was to conduct an animal safety study using two second generation photosensitizers, talaporfin sodium and verteporfin, to assess the risks of pancreatic PDT by looking at injury to organs adjacent to the pancreas and assessing recovery from PDT treatment of the pancreas. The Syrian Golden hamster animal model was used to compare the results of this research to previous work by other authors. The study design incorporated a number of additional experiments, including quantitative tissue fluorescence techniques, plasma level analysis and histopathology techniques. The methods for the animal safety study were similar to the approach used in the clinical setting and provided vital data on the likely risks and side effects of phototherapy in humans. The first study, looking at talaporfin sodium, found likely risks of duodenal injury, gastric injury and death with a limited effect on normal pancreas at photosensitizer doses likely to be employed for pancreatic cancer PDT. The second study, using verteporfin, found similar results with a more potent effect on the normal pancreas at studied drug doses. Both agents had short drug-light intervals, ranging from 15 minutes to 2 hours, reducing the need for pre-treatment hospitalization and short photosensitivity periods of about one to two weeks. Some animals suffered minor cutaneous photosensitivity injuries. A human pancreatic cancer PDT pilot study is feasible and the risks and complications should be acceptable.

Multi-step photoinduced electron transfer takes place over a large distance in the photosynthetic reaction centres (PRCs). Electron donor in this life-spending event is the photo-excited 'special pair', a unit of two electronically coupled porphyrinoid chromophores. Bacteriopheophytin and two quinone molecules function as electron acceptors and contribute to the charge separation with almost unit quantum efficiency. The natural photosynthetic reaction centre is the most sophisticated molecular electronic device to date and interest is high in increasing our understanding of the basic quantum mechanical principles behind efficient electron transfer and ultimately copying Nature and construct similar efficient devices. Two main approaches towards a better understanding of the mechanisms involved have been taken. The more biological disciplines isolate, cultivate and alternate reaction centres whereas synthetic chemists prefer to construct well-defined models that mimic certain aspects of the reaction centres. Such a synthetic approach is described in the 'Synthesis of Advanced 'Special Pair' Models for the Photosynthetic Reaction Centre'. The aspect to be mimicked is the 'special pair'. One or two porphyrins in a well-defined spatial disposition (kinked or non-kinked in respect to each other) were to act as electron donor in rigid bichromophoric and trichromophoric systems. A tetracyanonaphthoquinodimethane (TCNQ) unit was employed as the electron acceptor in the series of dyads synthesised. The TCNQ acceptor was replaced by a naphthoquinone (NQ) primary acceptor covalently linked to a TCNQ secondary electron acceptor in the series of triads. Rigid norbornylogous bridges held the chromophores in place and Diels-Alder methodology as well as condensation reactions were applied to link donor, bridge and acceptor components. Despite larger interchromophoric separation than in the natural 'special pair', the two porphyrin chromophores of the series of 'special pair' dyads show some interaction and thereby prove the success of our approach towards 'special pair' mimics. Strong fluorescence quenching in the porphyrin-TCNQ dyads indicates the sought after electron transfer process. A number of synthetic problems experienced and overcome in the synthesis of the series of triads led to discovery of a one-step 'bis-ketonisation' from an olefin under Sharpless bis-hydroxylation conditions with N-methylmorpholine-N-oxide. High pressure was applied to circumvent a lack of reactivity in the condensation reaction used to attach the porphyrin moieties (one or two) to the donor backbone. For the linkage of donor, bridge and acceptor component, a procedure was developed and successfully applied to give the giant mono-porphyrin-NQ-TCNQ trichromophore. In a similar manner 'special pair' trichromophoric systems should be available as part of future work.